Research

Modular expansion of the cerebral cortex

FGFR dominant negative transgenic mice have decreased cortical size and loss of pyramidal cells within layers III and V

Fibroblast Growth Factors (FGFs) promote cortical growth by increasing the generation of excitatory pyramidal cells from neural precursors (Vaccarino et al, 1999). Increasing or decreasing the expression of FGF2 and its cognate receptors increases or decreases, respectively, the number of excitatory pyramidal neurons in the cerebral cortex. These neurons form the core of cortical columns, surrounded by a “curtain” of inhibitory neurons and astrocytes. We have developed mouse mutants lacking the FGF receptors in neuroepithelial cells or radial glial cells of the forebrain and cerebellum. The mutants have decreased cortical volume and neuron number, most prominently in prefrontal cortex, and develop motor hyperactivity and various types of cognitive/motor impairments.

The potential of stem/progenitor cells to generate excitatory neurons in response to FGF signaling decreases, but it is not completely lost, during postnatal development. We have uncovered a surprising ability of postnatal GAP+ neural stem cells to generate neurons throughout the brain. The ability of these cells to respond to enriched environmental conditions is a focus of current investigations.

Regulation of neural stem cells during hypoxia-induced plasticity

stereological quantification of proliferating cells in the subventricular zone after hypoxic rearing

Brain damage caused by low oxygen (hypoxia) in the perinatal period is common in premature children and is a risk factor for cognitive handicap, tic disorders and hyperactivity. In our mouse model of perinatal hypoxia, the initial loss of cortical neurons is repaired in the weeks following the insult, revealing an unexpected capacity of the juvenile brain to recover (Fagel et al, 2006). GFAP+ neural stem cells and progenitors increase their proliferation and generate more neurons in the hypoxia recovery period, replacing those that are lost.

Increase in Dcx+ neuronal progenitors in the subventricular zone arising from GFAP+ cells marked with beta gal after the hypoxic insult

FGF signaling is up-regulated in stem cells and neural precursors and is required for their proliferation in response to the insult. Using inducible recombination via the GCE mouse model, we are investigating the role of growth factor receptor signaling in stem and progenitor cells after a postnatal hypoxic injury.

Development and function of inhibitory neuronal systems in the human brain and in mouse models

decrease in parvalbumin neurons in the caudate nucleus of TS as compared to NC analyzed by stereological methods]

Postmortem human brain stereological analyses have shown a deficit of parvalbumin inhibitory neurons in the striatum in 4 individuals with Tourette syndrome (TS), as compared to matched normal controls (NC) (Kalanithi et al, 2005).

We are investigating genetic and environmental factors affecting inhibitory neuron development using animal models. The conditional deletion of FGF receptor 1 from radial glial cells and cortical astrocytes causes an enduring loss of cortical parvalbumin inhibitory neurons which is accompanied by locomotor hyperactivity and learning impairments (Muller Smith et al, 2008). Altered number or distribution of specific classes of inhibitory interneurons in basal ganglia may underlie disorders of behavioral inhibitions, such as ADHD and Tourette syndrome. Aberrant genesis, survival or maturation of specific classes of inhibitory interneurons in cortex may underlie disordered thought and cognition present in schizophrenia.

correlation of actitivty scores with cortical parvalbumin neuron number in FGF receptor 1 mutants and wild types